1. Field of the Invention
The present invention relates to cataract surgery, specifically to compositions and methods for preventing proliferation of remnant lens epithelial cells occurring after cataract surgery. More specifically, the invention relates to the use of a combination for prevention of posterior capular opacification, particularly for surgically difficult cases.
2. Background of the Art
A natural lens is enveloped in a structure called the lens capsule, which is the basement membrane of lens epithelial cells, and held behind the iris and in front of the vitreous by a suspensory ligament called the zonules. The inside of the lens capsule consists of lens epithelial cells and lens fibers. Lens epithelial cells form a monolayer underlying the lens capsule from the anterior pole to the equator of the lens. Lens fibers occupy the rest of the inside of the lens capsule. Lens epithelial cells become elongated in the equator of the lens and turn into lens fibers. As well as the morphological change, lens epithelial cells show the alteration in biochemical features. That is, protein synthesis of lens epithelial cells greatly changes toward the lens equator. These morphological and biochemical changes are called differentiation. In an area between the anterior pole and the lens equator, lens epithelial cells continue to undergo cell mitosis throughout life. This area is called germinate zone. Lens epithelial cells that underwent cell mitosis in the germinate zone gradually move toward the lens equator and differentiate into lens fibers.
Lens fibers are divided into two parts; the lens cortex and the lens nucleus. The lens cortex is a relatively soft tissue that consists of young lens fibers located near the lens equator. These fibers accumulate throughout life and gradually lose their intracellular organelles moving toward the center of the lens forming a hard, closely packed lamellar structure called the lens nucleus.
In the prevailing cataract surgical procedure, i.e., extracapsular cataract extraction, an incision is made in the anterior part of the eye, i.e., the cornea, the sclera or the corneal scleral junction. A viscoelastic material is then introduced into the anterior chamber to maintain the anterior chamber depth. An opening is then made in the lens capsule. This procedure is called capsulotomy or capsulorhexis. Following capsulotomy, the clouded lens nucleus and lens cortex, mainly the lens nucleus, are fragmented by phacoemulsification and taken out of the eye, or simply delivered through the lens capsular opening when the nucleus is too hard to be fragmented. The lens cortex is then removed by using an irrigation and aspiration device while the anterior chamber and the lens capsular bag are irrigated with a physiological solution. If applicable, an intraocular lens (artificial lens) is inserted inside the remaining lens capsular bag after the lens capsular bag, is filled with a viscoelastic material. The term "lens capsular bag" means, herein, the lens capsule in which at least one opening or one hole is made. In the prevailing cataract surgical procedure, lens epithelial cells cannot be separated from the lens capsule so that postoperatively the remnant lens epithelial cells on the lens capsule proliferate and/or migrate toward the center on the posterior lens capsule. Due to the proliferated lens epithelial cells, the residual lens capsule becomes opacified, which obstructs the visual axis and causes a visual disturbance. This is called posterior capsular opacification or secondary cataract. The primary object of the present invention is to develop compositions and methods to prevent the proliferation of remnant lens epithelial cells following cataract surgery.
More than 1.3 million cataract surgeries are performed in the United States annually. Of patients who undergo cataract surgery, between the 20 and 40% develop posterior capsular opacification within 34 years postoperatively (Cataract Management Guideline Panel, Ophthalmology, 100 Suppl., 52s-55s, 273s-286s, 1993). In the current clinical standard, patients who develop posterior capsular opacification are treated by YAG laser capsulotomy. In this procedure the opacified residual lens capsule is disrupted by a YAG laser and the visual axis is cleared. However, YAG laser capsulotomy exposes patients to the risk of complications that can lead to severe visual impairment or loss of vision, such as retinal detachment, pupillary block glaucoma and cystoid macular edema (Cataract Management Guideline Panel 1993). Other complications associated with YAG laser capsulotomy include damage to implanted intraocular lenses resulting in glare and photophobia, dislocation of intraocular lenses, iritis, vitritis, corneal edema, iris damage and rupture of the anterior hyaloid face (Cataract Management Guideline Panel 1993). From an economic point of view, development of a procedure to prevent posterior capsular opacification reduces the medical costs related to YAG laser capsulotomy, including the costs for the treatment, its complications, and YAG laser equipment.
Accordingly, there is a great need for a way to prevent posterior capsular opacification.
There are mainly two approaches to prevent posterior capsular opacification; surgical and pharmacological approaches. As surgical approach, use of various surgical instruments and the application of laser, ultrasound and/or freezing techniques have been tried to separate and/or destroy the lens epithelial cells that remain attached to the lens, capsule. These attempts have turned out to be of little or no success.
As pharmacological approach, a variety of agents have been applied to destroy, kill, or separate the lens epithelial cells. However, most of these agents were not working) specific to the lens epithelial cells and, when an agent was used at an appropriate concentration to kill or destroy the lens epithelial cells, other surrounding eye tissues were damaged. In this regard, the use of a toxin-conjugated antibody against lens epithelial cells, i.e., immunotoxin, is a real possibility to specifically destroy the lens epithelial cells and prevent posterior capsular opacification. A recent clinical study indicates that the application of a ricin-conjugated antibody reduced the incidence of posterior capsular opacification but prevention of opacification was not complete (Ocular Surgery News, November 1, page 58, 1996).
Another pharmacological approach is to separate lens epithelial cells from the lens capsule. Ethylenediamine tetraacetic acid (EDTA) was included in an irrigative solution and a simulated extracapsular cataract extraction was performed to separate lens epithelial cells (Humphry et al., Br. J. Ophthalmol., 72:406-8, 1988). In other attempts, EDTA was used with a viscoelastic material (U.S. Pat. No. 5,204,331 to Nishi et al., 1993; Nishi et al., J. Cataract Refract Surg., 19:56-61, 1993), or simply introduced into the lens capsular bag (Wee et al., Invest. Ophthalmol. Vis. Sci., 34:887, 1993). When an EDTA solution was included in an irrigative solution and a simulated extracapsular cataract extraction was performed in cadaver eyes, the anterior lens epithelial cells could be separated (Humphry et al., 1988).
Enzymes such as trypsin (Humphry et al., 1988) and DISPASE.RTM. (Protease) (Nishi et al., Dev. Ophthalmol., 22:101-105, 1991a, Ophthalmic Surg., 22:444-50, 1991b) were also used to separate lens epithelial cells. When a 2% trypsin solution was included in an irrigative solution and a simulated extracapsular cataract extraction was performed in cadaver eyes, lens epithelial cells had been stripped in places. The cell separation was partially successful. Indeed, the zonules were damaged by the trypsin solution (Humphry et al., 1988). The use of an active enzyme can be a problem even when an enzyme solution is introduced into the lens capsular bag because an active enzyme can damage the zonules where the zonules are located in the lens capsule. A substantial problem in using an active enzyme was that the enzyme damaged a tissue or cells where a treating solution had contact.
According to U.S. Pat. No. 4,909,784 to Dubroff 1990, when a cell-killing substance is introduced into the lens capsule through a small hole, lens epithelial cells are killed. A viscoelastic material that is introduced into the anterior chamber prevents any of the substance escaping from the lens capsule and prevents damage to the corneal endothelium. In related patents (U.S. Pat. No. 4,909,784 to Dubroff 1990, U.S. Pat. No. 5,013,295 to Dubroff 1991), a syringe to remove the introduced substance from the lens capsule through a small hole was disclosed. However, physically and technically, it is difficult to efficiently remove the substance introduced into the lens capsular bag before capsulotomy without damaging the lens capsule. Therefore, the remaining substance can escape from the lens capsular bag and damage the cells and tissues facing the anterior chamber during and after capsulotomy. Thus, there is a great need for a way to prevent damage to cells and tissues during and after capsulotomy.
Surgically difficult cases
One of the most frequent complications in the prevailing cataract surgery is the proliferation of lens epithelial cells following cataract surgery. Lens epithelial cells that remain in the lens capsular bag at the end of the surgery proliferate on the posterior lens capsule and obstruct the visual axis postoperatively. It is called posterior capsular opacification or secondary cataract. It causes visual disturbance or glare. When an eye develops posterior capsular opacification, the patient is treated by YAG laser capsulotomy. However, the YAG laser treatment exposes patients to the risk of severe visual impairment or loss of vision to develop retinal detachment, glaucoma and cystoid macula edema. Accordingly, there is a great need to develop a method and a composition to prevent posterior capsular opacification.
It has been reported that the incidence of YAG laser capsulotomy can be reduced by implanting an intraocular lens (IOL) with truncated sharp optic edges such as AcrySof.RTM. IOLs (Alcon Lab.) and CeeOn.RTM. silicone IOLs (Pharmacia & Upjohn Inc.). However, according to the clinical trials of these IOLs, still YAG laser capsulotomy is required in 10% or more of patients who undergo cataract surgery (Oshika et al., J Cataract Refract Surg. 22:104-109,1998.). In pediatric cases with implantation of AcrySof.RTM. IOLs, 25% of patients require YAG laser capsulotomy (Cataract & Refractive Surgery, Euro Times, May-June 1999, p10). It was recently suggested that development of posterior capsular opacification would be reduced by implanting a convex-plano (plano-posterior) IOL in eyes in which continuous circular (or curvilinear) capsulorhexis was performed (Yamada et al., J Cataract Refract Surg. 21:697-700,1995. Nagata et al., Jpn J Ophthalmol. 40:397-403,1996.). Other devices and IOLs to prevent posterior capsular opacification, e.g., capsular ring, have been developed. However, the efficacy of the devices and the IOLs has not yet been established or the clinical outcome was not successful (Born et al., J Cataract Refract Surg. 16:188-192,1990. Maltzman et al., J Cataract Refract Surg. 15:644-646,1989.). Accordingly, elimination of YAG laser capsulotomy is not achieved by simply implanting an IOL with the truncated optic design or other devices and IOLs. For prevention of posterior capsular opacification, compositions and methods were disclosed by the present inventor in U.S. patent application Ser. No. 09/017,716. The disclosed methods substantially successfully prevent posterior capsular opacification. However, there can be some difficult surgical conditions and challenging cases that may result in incomplete removal or separation of lens epithelial cells. In order to eliminate YAG laser capsulotomy, inhibition of posterior capsular opacification has to be secured in any patient. Approximately 3.7 million cataract surgeries are performed annually worldwide and patients who develop posterior capsular opacification due to incomplete removal or separation of lens epithelial cells cannot be ignored. It is because, unless elimination of YAG laser capsulotomy is achieved, expensive YAG laser equipment has to be reserved for the back-up treatment. This aspect has not been seriously considered in the literature. The present invention provides the improved methods for prevention of posterior capsular opacification to eliminate YAG laser capsulotomy. The methods are effective in surgically difficult situations and cases and challenging cases.